This request for renewal of an RSA is based on a continuing commitment to enhance understanding of cognitive processes in the human brain through behavioral, anatomical, and physiological research in nonhuman primates. The main focus of this research program is on the structural and physiological mechanisms of the prefrontal cortex (PFC), the area shown in numerous clinical and experimental studies to be essential for the cognitive processes of comprehension, reasoning, and intentionality. I plan to pursue the several avenues of research already opened by our current studies on working memory at the areal, circuit, cellular and synaptic levels of analysis. Specific issues explore: (1) the domain specificity of visual memory circuits and memory modules within the PFC; (2) the localization and mechanisms of auditory working memory systems; (3) the organization of these levels in relation to motor systems; (4) the maintenance of the memory trace, the source of pre- and post-response signals and the interactions between PFC and other regions of the brain; and (5) the elucidation of working memory domains in humans. As in the past, these aims will be accomplished through a multidisciplinary research strategy. Functional analyses rely on single cell recording and 2- deoxyglucose metabolic labeling in conjunction with a variety of precisely controlled sensory-guided and memory-guided behavioral paradigms. The analyses are supported by detailed knowledge of the local and long-tract connections and synaptic architecture of prefrontal circuits. Advanced tracing with PHA-L, biotinylated PHA-L and dextrans and/or fluorescent dyes combined with immunocytochemical methodology will be employed in vivo and in fixed tissue slices and subjected to analysis at both the light and electronmicroscopic analyses. Overall, the proposed research effort is expected to illuminate the structure and function of the prefrontal cortex and advance our understanding of the neurobiological basis of normal and disordered cognition.